Neurotransmitters

Chemical Neurotransmitters

Neurotransmitters are natural monoamine chemicals found in food. In the brain they serve as messengers to relay electrical nerve impulses along the neuron axon. The nerve impulse travels along the axon (nerve fibre) to the other end of the neuron where neurotransmitters are released from the pre-synaptic neuron into the synapse. Some neurotransmitter passes into the post-synaptic neuron, some is metabolised (broken down) by the monoamine oxidase (MAO) enzyme and some is reabsorbed back into the pre-synaptic neuron into storage vesicles. Dopamine,serotonin, noradrenaline and adrenaline are all monoamine neurotransmitters.The building blocks for these monoamines are phenylalanine which in turn is transformed to tyrosine.

There are ten million neurons in the brain.

In order for the body to function smoothly there needs to be optimal neurotransmitters in the brain.

Although antipsychotics are primarily designed to target the dopamine neurons other neurotransmitter neurons such as histamine, serotonin, muscarinic, acetylcholine and noradrenaline receptor neurons are affected.

Monoamine Oxidase Enzymes (MAO) These are essential for healthy psychological and physical functioning, since they break down excessive amounts of monoamine neurotransmitters in the body and brain. There are two types of MAO - MAO-A and MAO-B and both are found in the liver, gut, cell membranes and neurons. MAO-B breaks down phenylalanine, a building block for dopamine: MAO-A breaks down serotonin and noradrenaline. Both MAO-A and MAO-B breaks down dopamine, adrenaline and also tyramine, which is involved with noradrenaline. Any interference with MAO results in excessive amounts of all these neurotransmitters in the brain and body.

Low levels of MAO have been recorded in 'schizophrenia' (Giillin1976, Meltzer et al 1982); however Meltzer refuted these findings a year later in a co-authored article (Jackman et al 1983). This was replicated in an article by Elman 1999. Paik 1988 associated these low levels in the brain with neurolepticed patients.

Other articles indicate that some neuroleptics inhibit MAO enzyme (Lieberman et al 2006, Meszaros et al 1998). It appears that neuroleptics prevent the break down of these monoamine neurotransmitters causing increased levels and results in physical and psychological ill health.

1. Psychological functions: Feelings of motivation Feelings of pleasure in association with love Addiction Feelings of attachment Feelings of altruism (unselfish concern for others) Feelings of 'wanting' 2. Physical Functions: Control of coordination of voluntary movements Aids the clearance of excess mucus in the lungs

Neuroleptics used long term causes respiratory problems such as respiratory dyskinesia which makes breathing laboured and also increased risks of developing respiratory illnesses. As dopamine levels become depleted this has a disruption effect upon ACH and more ACH is released. Some atypical neuroleptics in addition strong anticholinergic properties; disruption of the acetylcholine circuits over stimulates acetylcholine transmission so making and releasing more acetylcholine in the brain. Excess mucus results in the lungs and because excess acetylcholine depletes dopamine there is insufficient dopamine to mop up the lung mucous. It is therefore not schizophrenia per se which causes respiratory disease or more prone to getting swine flu as the DH tends to focus on but the neuroleptics which causes this 'adverse effect'.

Action: Neuroleptics block dopamine post receptor sites on each neuron reducing their ability to take up dopamine. The normal action of relaying impulses is disrupted, which in turn prevents the release of dopamine into the next synapse. In order to redress the neuroleptic interference, more receptor cells are created. When neuroleptics are used long-term, the activity of the neurons become less active. The insidious blockage of the receptor neurons causes insidious damage to each neuron.

Different neuroleptics block different dopamine receptors in varying degrees of tenacity. The whole process results in dopamine depletion in various dopamine pathways, disabling the dopamine functions. The deficiency of dopamine occurs by a process known as "depolarization blockade".

Neuroleptics prescribed long term reduce dopamine; in theory this would potentially result in decreased amounts of noradrenaline and adrenaline in the body. However Clozapine patients show increased noradrenaline levels (Elman 1999). This situation is highly likely due to the the inhibitory action of neuroleptics on the MAO enzymes. Under normal circumstances dopamine is broken down by MAO-A and MAO-B.

Food sources Dopamine rich foods include all proteins (meat, milk products, fish, beans, nuts, soy products). 3-4 ounces of protein will help you to feel energized, more alert and more assertive. http://www.thethinkingbusiness.co.uk/brainfoods.htm Phenylalanine is an amino acid and found in the above foods. It is also found in the synthetic sweetener aspartame, which is often used in sugar free foods and fluids (NutraSweet). Phenylalanine is the precursor to tyrosine which in turn is the precursor to dopamine.

The following site: mentalhealth.emedtv.com/phenylalanine/phenylalanine-drug-interactions.html depicts how some neuroleptics can cause interactions with phenylalanine that result in potentially dangerous side effects. These neuroleptics include Clozapine, Risperidone, Olanzapine, Quetiapine and Abilify. Studies have shown that phenylalanine may worsen TD http:// mental-health.emedtv.com/phenylalanine/phenylalanine-side-effects.html

Phenylketonuria (PKU) is a genetic disorder which results in an inability to breakdown phenylalanine. Excess phenylalanine levels is toxic, causes mobility difficulties, irritability, agitated behaviour, EEG abnormalities, reduces skin pigment and also a musty unpleasant odour. This disorder is diagnosed at birth by the Guthrie test and treatment is a diet free of phenylalanine.

Since neuroleptics reduce the activity of MAO-B, excessive amounts of phenylalanine results in neurolepticed persons. Increased phenylalanine levels interferes with the availability of tryptophan, which then results in low levels of serotonin. Low levels of serotonin is known to causes aggression.

Aggression, hostility and irritability in mental health is treated with ever increasing psychotropic medications. I think this is a continuous vicious expanding circle and the only outcome for patients is in line with untreated phenylketonuria. Tardive Dyskinesia causes mobility difficulties, patients begin to loose their memories, have cognitive difficulties and the neuroleptics alter the brains structure.

I think it is reasonable for all patients treated with neuroleptics to have the Guthre test and if positive, to be prescribed a PKU diet in order to minimise the neuroleptic induced PKU.

Noradrenaline (Norepinephrine) Neurotransmitter Noradrenaline was discovered in 1946 and besides being a major neurotransmitter in the Central Nervous System is also a hormone when released by the adrenal medulla gland. The noradrenergic pathways serve the cerebral cortex, limbic system and the brain stem.

In the brain, noradrenaline is concerned with forming memories, regulating sleep, levels of arousal and attention; depletion is associated with lack of drive and initiative. Noradrenaline outside the brain is associated with the Sympathetic Nervous System, being connected with the 'Fight and flight' responses. Under normal circumstances noradrenaline is broken down by MAO-A.

Dopamine is an immediate precursor of noradrenaline (the body needs dopamine to make noradrenaline), and likewise, noradrenaline is a precursor of the hormone adrenaline (Craft et al 2004); i.e. the body needs noradrenaline to make adrenaline. Therefore, dopamine is a precursor of adrenaline.

Neuroleptics deplete noradrenaline. Noradrenaline depletion causes:

Lack of drive and initiative Inability to form memories Disregulation of sleep Low levels of arousal and attention and therefore lack of ability to react in the face of danger. (Bishnoi et al 2007)

Functions: The functions of serotonin in the body are regulation of sleep/awake, temperature, appetite, emotions, mood, sleep and our subjective perception in relation in the world and other people. Serotonin is produced from the pineal gland in the brain and 5-HT2 serotonin receptors are located in the heart, lungs, gut and blood vessels as well as the brain. Under normal circumstances serotonin is broken down by MAO-A.

Neuroleptics disrupts the body's natural serotonin balance; the serotonin levels will deplete in chronic neuroleptic consumption (Croll et al 1997) or become excessive which results from raising neuroleptic doses or when two or more psychotropic drugs are combined.

Tryptophan is a precursor for serotonin and niacin. It is made by the body and found in various foods. Food sources: Chocolate, oats, bananas, dried dates, cottage cheese, red meat, fish,milk, peanuts, dates, milk, eggs, chickpeas, yoghurt, sunflower seeds, pumpkin seeds and cottage cheese. Tryptophan is a routine constituent of most protein-based foods or dietary proteins. http://www.iscid.org/encyclopedia/Tryptophan

Aspartame, a phenylalanine source, is believed to decrease the availability of tryptophan which results in serotonin inhibition.www.mcmanweb.com/diet_coke.html "Low levels of serotonin in the brain have been associated with an increased susceptibility to impulsive behaviour, aggression, over eating, alcohol abuse and violent suicide". /www.life-enhancement.com/article_template.asp?ID=208

The neuroleptics which affect serotonin 5-HT2 neuron receptors are risperidone, clozapine, olanzapine, quetiapine and clopixol. When neuroleptics are prescribed the normal sleep patternis disrupted - many people in receipt of neuroleptics sleep well overthe average eight hours and additionally have difficulty in getting upat a reasonable hour in the morning.Tyramine

Tyramine is a breakdown of tyrosine and when MAO-A is inhibited, noradrenaline is released from storage vesicles. This can result in blood pressure spiking to dangerous levels after eating foods high in tyramine or tryptophan.

The blood pressure spikes rapidly which can last from one minute to many minutes. This may precipitate a Cerebral Vascular Accident (stroke) resulting in death; headaches which feel like a ball is bouncing back and forth inside the skull, feeling sick, stiff neck, heart palpitations, profuse sweating, chest pain and insomnia. When patients are prescribed Monoamine Oxidase Inhibitors (MAOI) antidepressant medication, patients need to go on a low tyramine diet to avoid the potentially fatal hypertensive crisis. The symptoms described above results from the dysregulation of the Autonomic Nervous System.

In addition the inhibition of tyramine breakdown by low levels of MAO activity, tyramine is metabolised by the CYP2D6 pathway (Hiroi 1998). If a person is a Poor Metaboliser for the the CYP2D6, and/or when neuroleptics are prescribed tyramine levels will increase, because the body is unable to get rid of excess tyramine. Excess tyramine releases dopamine, noradrenaline adrenaline from storage vesicles.

Acetylcholine, the first neurotransmitter discovered in 1921, is found in the Central Nervous System (CNS = brain + spinal chord), Autonomic Nervous System(ANS) and the Peripheral Nervous System (PNS) (nerve axons outside of the CNS). Functions Acetylcholine within the PNS facilitates the contraction and relaxation of the involuntary or smooth muscles of the internal organs, such as the lungs, heart, intestines, bladder,eyes, salivary glands and blood capillaries. Other functions within the CNS include memory, thought and learning processes.

Excess acetylcholine causes increased mucous production and constriction of the bronchioles within the lungs, causing breathing difficulties, decreases the heart rate, the pupils dilate and also an increase in sweating (

Shibasaki 2001).

In Parkinsons disease, dopamine gradually depletes causing an imbalance between the normal interactions with dopamine and ACH. These neurotransmitters normally work together coordinating body movements. As dopamine becomes depleted, acetylcholine increases causing the symptoms of Parkinson's disease such as body tremors and drooling, slurred speech and mobility difficulty.

One common typical neuroleptic side effect is EPS. These neuroleptics include Largactil, Haloperidol and Acuphase, although atypicalmedication such as Clozapine can also cause EPS. These side effects include perpetual body tremors (varies from being hardly perceptible to obvious shaking), drooling, difficulty with mobility and flat expression. These are the typical symptoms ofParkinson's disease. These side effects suggests neuroleptics increase Ach.

Anticholinergic drugs are prescribed to reduce the symptoms of Parkinson's disease - these same drugs are also prescribed to reduce the symptoms of neuroleptic induced EPS. Anticholinergic drugs have their own side effects and within the PNS, include blurred vision, headaches, dry eyes and dry mouth, heart rate increase, decreased sweating, difficulty in urinating and constipation (Lieberman 2004). Within the CNS the side effects include confusion, memory impairment, attention deficit and impaired concentration. (Lieberman 2004).

Atypical neuroleptics have anticholinergic properties which cause the anticholinergic side effects described above. Different neuroleptics have different degrees of anticholinergic strength:Risperidone has a low level whilst Clozapine has a high anticholinergic level.

Neuroleptics have been associated with blocking the Ach muscarinic post- receptors; thus they have been thought they have anticholinetrgic properties and block Ach secretion. This theory is wrong since it is the pre receptors which are blocked; this causes a release of excessive Ach from the storage vesicles in the Pre receptor neuron into the synaptic gap. Back in 1993 Imperato, wrote an article finding neuroleptics increased Ach in the brain (Imperato 1993).

Incecticides are designed to disrupt the insect's nervous system by creating excessive acetylcholine - the insect turns on its back and all the legs move rapidly before dying.

Sarin dysregulates the functions of the PNS, ANS and the CNS, works on the same principle and is potentially irreversible. People exposed to Sarin drool, feel nauseous, vomit, urinate excessively, have diarrhoea, sweat,slurred speech, rhinorrhea, eye and head pain, abdominal cramps, blurred/double vision and difficulty in breathing - these are the ANS muscarinic symptoms. The body feels weak, twitches, high blood pressure and a fast heart rate - ANS nicotinic symptoms. CNS symptoms include confusion, irritability, slurred speech, memory loss and impaired judgement. Excessive levels of sarin leads to flaccid paralysis, seizures which precedes death from the inability of the muscles in chest wall to expand and contract. Death occurs from respiratory failure. The CPK and WBC levels are raised.

Insecticides and sarin are known as OP (organophosphates). Emerson et al found that men aged 30-50 years were more likely to attempt suicide when exposed to organophosphates.

NMS (Neuro Malignant Syndrome) - a side effect of neuroleptics has very similar signs and symptoms as OP. NMS is potentially fatal and is due to the body being unable to metabolise neuroleptics.

Neurotransmitter Pathways Bundles of neurotransmitter neuronal pathways traverse the brain. The pathways link one part of the brain to another. Each neurotransmitter has its own pathway. Dopamine Pathways The major dopaminergic pathways are the mesolimbic pathway, mesocortcal pathway, the tuberoinfundibular pathway and the nigrostriatal pathway. There are different dopamine receptor cells in different pathways.

Neuroleptics are designed to target the mesolimbic and the mesocortical pathways. There are tables which show to what extent different neuroleptics impact the different receptor cells (Jackson 2005, pg 173).

Summary Through their impact on neurotransmitters, neuroleptics have a negative impact upon all the workings of the brain; the functioning in the cerebrum, mid brain, brain stem are all affected which in turn impacts upon our mind and our body organs.

A comprehensive book about how all psychotropic medications including neuroleptics impair the bodies natural functioning can be read in: